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Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts

Nature Genetics volume 41, pages 1350–1353 (2009)Cite this article

Abstract

Induced pluripotent stem (iPS) cells are derived by epigenetic reprogramming, but their DNA methylation patterns have not yet been analyzed on a genome-wide scale. Here, we find substantial hypermethylation and hypomethylation of cytosine-phosphate-guanine (CpG) island shores in nine human iPS cell lines as compared to their parental fibroblasts. The differentially methylated regions (DMRs) in the reprogrammed cells (denoted R-DMRs) were significantly enriched in tissue-specific (T-DMRs; 2.6-fold, P < 10−4) and cancer-specific DMRs (C-DMRs; 3.6-fold, P < 10−4). Notably, even though the iPS cells are derived from fibroblasts, their R-DMRs can distinguish between normal brain, liver and spleen cells and between colon cancer and normal colon cells. Thus, many DMRs are broadly involved in tissue differentiation, epigenetic reprogramming and cancer. We observed colocalization of hypomethylated R-DMRs with hypermethylated C-DMRs and bivalent chromatin marks, and colocalization of hypermethylated R-DMRs with hypomethylated C-DMRs and the absence of bivalent marks, suggesting two mechanisms for epigenetic reprogramming in iPS cells and cancer.

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Figure 1: Reprogramming differentially methylated regions (R-DMRs).
Figure 2: DNA methylation at R-DMRs distinguishes normal tissues from each other and colon cancer from normal colon.

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Acknowledgements

This research was supported by the US National Institutes of Health (A.P.F. and G.Q.D.). G.Q.D affiliations include the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; the Division of Hematology, Brigham and Women's Hospital; Harvard Stem Cell Institute; and the Manton Center for Orphan Disease Research.

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Author notes

  1. Akiko Doi, In-Hyun Park and Bo Wen: These authors contributed equally to this work.

  2. George Q Daley and Andrew P Feinberg: These authors jointly supervised this work.

Authors and Affiliations

  1. Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Akiko Doi, Bo Wen, Peter Murakami, Brian Herb, Christine Ladd-Acosta & Andrew P Feinberg

  2. Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Howard Hughes Medical Institute, Boston, Massachusetts, USA

    In-Hyun Park, Junsung Rho, Sabine Loewer, Justine Miller, Thorsten Schlaeger & George Q Daley

  3. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

    Martin J Aryee & Rafael Irizarry

  4. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA

    Martin J Aryee

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  1. Akiko Doi
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Contributions

A.D. performed CHARM, bisulfite pyrosequencing and data analysis; B.W. performed initial experiments and helped design and analyze the study; I.-H.P., J.R., S.L., J.M. and T.S. performed cell culture and prepared nucleic acids; P.M., M.J.A., R.I., B.H. and C.L.-A. performed statistical analysis; G.Q.D. and A.P.F. designed the study, supervised the experiments and wrote the paper with A.D. and B.W.

Corresponding authors

Correspondence to George Q Daley or Andrew P Feinberg.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3, Supplementary Tables 3–4, 7,9–10 (PDF 1297 kb)

Supplementary Table 1

Reprogramming differentially methylated regions (R-DMRs). (XLS 914 kb)

Supplementary Table 2

Gene ontology functional categories enriched in reprogramming differentially methylated regions (R-DMRs). (XLS 47 kb)

Supplementary Table 5

Regions of differential methylation between 3 additional iPS lines and the fibroblasts from which they were derived. (XLS 424 kb)

Supplementary Table 6

Regions of differential methylation between iPS cells and ES cells. (XLS 32 kb)

Supplementary Table 8

Relationship between differential gene expression and differential methylation at reprogramming differentially methylated regions (R-DMRs). (XLS 131 kb)

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Doi, A., Park, IH., Wen, B. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41, 1350–1353 (2009). https://doi.org/10.1038/ng.471

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